Project Summary Affecting over 1% of the world?s population, including 3 million Americans, schizophrenia is a debilitating psychiatric disorder characterized by an array of symptoms including hallucinations, delusions, difficulty expressing emotions, and deficits in attention and memory. Despite the currently available antipsychotics, patients suffering schizophrenia have a life expectancy 10 years lower than that of the general population, are prone to substance abuse, homelessness, and are at risk of suicide. As a result, both the toll exacted on the lives of individuals suffering from the disorder and the public health costs are substantial. There is currently no cure for schizophrenia, and research into the causes of the disease, including the anatomical and physiological disruptions in the brain, has been difficult because little is known about the underlying pathology of cells in patients. To elucidate the anatomical and physiological deficits found in the patients with schizophrenia, this proposal will develop a novel model for the disorder by transplanting reprogrammed human induced- Pluripotent Stem Cells (iPSCs) into an animal system and imaging the structure and function of these cells in vivo. In Aim 1, this project will develop the technologies needed to perform structural characteriation of human iPSC-derived neurons including developing methods to analyze neural circuit structure and anatomical dynamics. In Aim 2, this project will develop technologies needed to image the population calcium activity of human iPSC-derived neurons in vivo and develop new analysis methods for studying and characterizing this acitivity. In Aim 3, this project will apply these technologies to characterize the structure and spontaneous activity patterns of human iPSC-derived neurons in vivo. Taken together, this work will develop a powerful new platform for dissecting the structure and function of human neural circuits with the aims of understanding the neurobiological basis of schizophrenia.